靶向糖原合成激酶-3β的[18F]马来酰亚胺结构PET显像剂的研制

Dysregulation of glycogen synthase kinase-3β (GSK-3β) is implicated numerous human diseases, particularly in the pathogenesis of neurodegenerative and psychiatric disorders. Thus, development of GSK-3β radiotracers for positron emission tomography (PET) imaging is of paramount importance, because such a non-invasive imaging technique would quantify detection of enzyme’s activity. Prior work from our laboratories has demonstrated a [18F]-labeled maleimide GSK-3β PET tracer with potent binding and moderate brain uptake in rodents. Therefore, we propose that the [18F]-labeled maleimides inhibitors could be as promising GSK-3β PET tracers. Herein, we will design a series of incorporating a fluoroethyl group in maleimides as GSK-3β inhibitors using Autodock software, based on the co-crystal structure of GSK-3β and maleimide inhibitor. These inhibitors will be synthesized and biological evaluated in vitro for screening potential PET tracers with potent binding. The [18F]-labeled GSK-3β tracers will be radiolabeled with [18F] and imaged in rodents and nonhuman primates with PET. It's promising to get a [18F]-labeled GSK-3β PET tracer for cerebral diseases imaging.

糖原合成激酶-3β（GSK-3β）的失调涉及许多人类疾病，特别是在神经退行性疾病和精神类疾病的发病机理中起重要作用。发展靶向GSK-3β的正电子发射断层扫描（PET）显像剂可以活体内无创伤性定量检测GSK-3β的活性。本课题组前期研究发现了一种[18F]标记的马来酰亚胺结构GSK-3β显像剂具有高亲和性并且在大鼠脑部中度摄取。在此基础上，我们提出设想：[18F]标记马来酰亚胺结构抑制剂是有前景的GSK-3β PET显像剂。本课题以GSK-3β与马来酰亚胺抑制剂复合物的晶体结构为基础，用Autodock软件设计系列含氟乙基的马来酰亚胺结构GSK-3β抑制剂，合成、体外评估抑制剂筛选出高亲和力的潜在PET显像剂，[18F]标记得到GSK-3β PET显像剂并在啮齿类和非人灵长类动物体内进行PET显像，有望筛选出一种新型的GSK-3β PET显像剂用于脑疾病显像。

正电子发射断层显像（PET）通过正电子显像剂观察和研究体内生理机制，无创伤获得活体内代谢途径、生物分子机制、受体和酶的功能等信息。糖原合成激酶-3β（GSK-3β）的失调涉及许多人类疾病，特别是在神经退行性疾病和精神类疾病的发病机理中起重要作用。发展靶向GSK-3β的PET显像剂可以活体内无创伤性定量检测GSK-3β的活性。然而目前尚未成功研制出有效的GSK-3 PET探针，国内外报道的GSK-3 PET探针存在着不能穿过血脑屏障、脑内特异性差、摄取值低等不足。本团队一直致力于18F标记GSK-3 PET探针的研制，在前期工作的基础上进一步通过分子模拟软件设计和有机合成多种含氟的马来酰胺和异烟胺结构GSK-3β配体；体外测得配体与GSK-3β的结合力，选择亲和力在纳摩尔的配体经过[18F]标记制备得到探针，探针进一步在细胞和大鼠体内外评估其特异性以及药物动力学等特性，筛选出三种具有高亲和力、穿过血脑屏障和特异性的GSK-3β探针。该探针有望进一步在与GSK-3β相关疾病AD模型中显像研究与证实。有望对与GSK-3β相关疾病如AD的早期诊断、发病机制和疗效监控提供重要信息。本项目以通讯作者已发表SCI收录论文三篇、中文1篇，在申请中国发明专利2篇。